Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and provide paracrine support to surrounding non-vascular cells. Technical advances in the past 5 years in single-cell genomics and in in vivo genetic labelling have facilitated greater insights into endothelial cell development, plasticity and heterogeneity. These advances have also contributed to a new understanding of the timing of endothelial cell subtype differentiation and its relationship to the cell cycle. Identification of novel tissue-specific gene expression patterns in endothelial cells has led to the discovery of crucial signalling pathways and new interactions with other cell types that have key roles in both tissue maintenance and disease pathology. In this Review, we describe the latest findings in vascular endothelial cell development and diversity, which are often supported by large-scale, single-cell studies, and discuss the implications of these findings for vascular medicine. In addition, we highlight how techniques such as single-cell multimodal omics, which have become increasingly sophisticated over the past 2 years, are being utilized to study normal vascular physiology as well as functional perturbations in disease. 

/pdf/vascular-endothelial-cell-development-and-diversity-2cgdqjt7.pdf

Vascular endothelial cell development and diversity

This review summarizes current knowledge and future directions on the mechanisms that govern the interplay between m6A RNA modification, RNA folding, and protein–RNA interactions, focusing on the mechanisms and available quantitative information.

Interconnections between m6A RNA modification, RNA structure, and protein–RNA complex assembly

Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin

N6-methyldeoxyadenine (6mA) has recently been reported as a prevalent DNA modification in eukaryotes. The Tetrahymena thermophila MTA1 complex consisting of four subunits, namely MTA1, MTA9, p1, and p2, is the first identified eukaryotic 6mA methyltransferase (MTase) complex. Unlike the prokaryotic 6mA MTases which have been biochemically and structurally characterized, the operation mode of the MTA1 complex remains largely elusive. Here, we report the cryogenic electron microscopy structures of the quaternary MTA1 complex in S-adenosyl methionine (SAM)-bound (2.6 Å) and S-adenosyl homocysteine (SAH)-bound (2.8 Å) states. Using an AI-empowered integrative approach based on AlphaFold prediction and chemical cross-linking mass spectrometry, we further modeled a near-complete structure of the quaternary complex. Coupled with biochemical characterization, we revealed that MTA1 serves as the catalytic core, MTA1, MTA9, and p1 likely accommodate the substrate DNA, and p2 may facilitate the stabilization of MTA1. These results together offer insights into the molecular mechanism underpinning methylation by the MTA1 complex and the potential diversification of MTases for N6-adenine methylation. 

https://www.nature.com/articles/s41421-022-00516-w.pdf

Structural insights into DNA N6-adenine methylation by the MTA1 complex

Cuproptosis and Cu: a new paradigm in cellular death and their role in non-cancerous diseases

/pdf/ai-empowered-integrative-structural-characterization-of-m6a-3008avdt.pdf

AI-empowered integrative structural characterization of m6A methyltransferase complex

WTAP–VIRMA counteracts dsDNA binding of the m6A writer METTL3–METTL14 complex and maintains N6-adenosine methylation activity

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AI-empowered integrative structural characterization of m6A methyltransferase complex

Structural insights into DNA N6-adenine methylation by the MTA1 complex

WTAP–VIRMA counteracts dsDNA binding of the m6A writer METTL3–METTL14 complex and maintains N6-adenosine methylation activity